5-alkyl-1 6-fused cycloalkylene-tetrahydro-1 5-diazine salts

ABSTRACT

1-R,2,3-(-CH2-(CH2)N-CH2-)-TETRAHYDROPYRIMIDINIUM Y(-)   QUATERNARY AMMONIUM SALTS OF THE FORMULA: WHEREIN R IS A STRAIGHT OR BRANCHED ALKYL GROUP HAVING BETWEEN 10 TO 24 CARBON ATOMS IN THE STRAIGHT CHAIN, N IS A POSITIVE INTEGER OF FROM 1 TO 3; Y IS AN ACCEPTABLE ION; AND THE BROKEN LINE (---) INDICATES THAT THE CARBON-NITROGEN DOUBLE BOND RESONATES BETWEEN THE TWO NITROGEN ATOMS AND THE POSITIVE CHARGE IS DISTRIBUTED BETWEEN THE TWO NITROGENS; AND METHODS OF PREPARING SUCH METHODS BY THE REACTION OF A DIAZABICYCLOAKLENE WITH A SUBSTITUTED ALKANE. THE COMPOUNDS HAVE UTILITY AS ANTI-BACTERIAL AGENTS.

United States Patent Olfice 3,652,564 Patented Mar. 28, 1972 3,652,5645-ALKYL-1,6-FUSED CYCLOALKYLENE-TETRA- HYDRO-1,5-DIAZINE SALTS David J.Ellis, Mountain View, and David Rammler, Palo Alto, Calif., assiguors toSyntex Corporation, Panama, Panama No Drawing. Filed Dec. 1, 1969, Ser.No. 881,299 Int. Cl. C07d 51/46 US. Cl. 260251 A p 17 Claims ABSTRACT OFTHE DISCLOSURE Quaternary ammonium salts of the formula:

RN N Y This invention relates to novel alkyl substituted quaternaryammonium saltswhich have anti-bacterial activity. I

Inanother aspect, the invention relates to alkyl sub-, stitutedquaternary ammonium salts having the following general formula:

in which R is a straight or branched alkyl group having between 10 to 24carbon atoms in the straight chain, It is a positive integer of from 1to 3, and Y is an acceptable anion. The broken line indicates that thecarbon-nitrogen double bond resonates between the two nitrogen atoms andthe positive charge is distributed between the two nitrogens.

The preferred alkyl group is a straight chain alkyl of ten to 24 carbonatoms. Such alkyls include, for example,

n-decyl, n-hexadecyl, n-octadecyl, n-tetracosyl, and the like. Equallysuitable, though less preferred for economic reasons, are the branchedalkyls having a backbone of from 10 to 24 carbon atoms. The branchedgroups may be lower alkyls containing from one to 8 carbon atoms ormore, such as methyl, ethyl, n-propyl, isopropyl, nbutyl, sec-butyl,t-butyl, n-pentyl, n-heptyl, n-octyl and the like. Also suitable arecycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl, and thelike. One or more of these alkyl, or cycloalkyl groups, or mixturesthereof maybe attached at any site or combination of sites along the C-C backbone.

By the term acceptable anionis meant an anion which does not inhibit theanti-bacterial activity of the quaternary ammonium salt. Where theproduct of this invention is to be used in treating animals, etc., theanion is preferably a pharmaceutically acceptable anion.

The expression pharmaceutically acceptable anion, as used herein, refersto a pharmaceutically acceptable anion of an inorganic or organic acidconventionally used in the pharmaceutical art derived from acids, suchas, for example, sulfuric, hydrochloric, hydrobromic, hydroiodic,phosphoric, lactic, benzoic, acetic, propionic, maleic, malic, tartaric,citric, cyclohexylsulfamic, succinic, nicotinic, ascorbic acids, and thelike. Preferred pharmaeutically acceptable anions are bromide, andchloride. Additionally, preferred anions are sulfate, acetate, andlactate.

Where formulations containing the quaternary ammonium salt are to beused for disinfecting inanimate objects, the anion need not be limitedto a pharmaceutically acceptable anion. However, for reasons of safety,the anion should preferably be non-toxic.

Typical compounds of the present invention include5-decy1-1,5-diazabicyclo[5.4.0]undecenonium chloride,

S-decyll ,S-diazabicyclo 5 .4.0] undecenonium methyl sulfonate,

S-tetradecyl-1,5-diazabicyclo[4.4.0] decenonium iodide,

5-octadecyl-1,5-diazabicyclo[4.3.0]nonenonium bromide,

S-hexadecyl-l,5-diazabicyclo[4.4.0]decenonium sulfate,

5 lO-methylundecyl 1,5 -diazabicyclo [4.4.0]

decenonium bromide,

5- (5'-methyldecyl)-1,5-diazabicyclo [4.4.0] decenonium acetate,

5-( 16-methyloctadecyl) 1,5-diazabicyclo [4.4.0]

decenonium citrate,

5-(7,8'-dimethyltetradecyl)-1,5-diazabicyclo [4.4.0]

decenonium maleate,

5-(2-hexyldecyl)-1,5-diazabicyclo 4.3.0] nonenonium chloride,

5-(2,4,6-triethyldecyl)-l,5-diazabicyclo[4.3.0]

nonenonium lactate,

5-tricosyl-1,5-diazabicyclo[4.3 .0]nonenonium chloride,

S-eicosyl-l,5-diazabicyclo[5.4.0] undecenonium chloride,

5- 3 ',7,l1',15-tetramethylhexadecyl)- 1 ,S-diazabicyclo[5.4.0]undecenonium bromide,

5-(10'-cyclohexadecyl)-1,5-diazabicyclo[5.4.0]

undecenonium bromide,

5-(2'-hexyl-10-cyclopropyldecyl)-1,5-diazabicyclo [5.4.0] undecenoniumchloride, and the like.

The quaternary ammonium salts of Formula A can be prepared either by (1)a direct replacement reaction of a substituted alkane with adiazabicycloalkene of the following formula:

where n is a positive integer of from 1 to 3, or (2) by the replacementreaction of an alkane substituted with an easily replaceable radical anda diazabicycloalkene of Formula B, followed by a second reaction inwhich the anion of the salt thus formed is itself replaced by a secondanion. Suitable replaceable radicals are methanesulfonyloxy andp-toluenesulfonyloxy. These anions are easily replaced by such anions aschloride, bromide, and the like.

By method (1), preferred for obtaining the quaternary ammonium halide,an alkyl halide, such as alkyl bromide, chloride, or iodide, is directlyreacted with diazabicycloalkene to yield the correspondingdiazabicycloalkenonium halide.

The alkyl halide can be a primary or secondary halide. Higher percentageyields are obtained with the primary 'halide and therefore the primaryhalide is preferred. Particularly preferred, as they are most readilyobtainable are the primary halides of the straight chain alkanes.

By method (2), a methanesulfonyloxy alkane or a ptoluenesulfonyloxyalkane is reacted with a diazabicycloalkene to yield the' correspondingmethanesulfonate r p-toluene sulfonate salt respectively. The anion ofthe salt is then replaced by conventional techniques. By way of example,to obtain the salt of other acceptable anions, the sulfonate salt can besubject to a strongly basic ion exchange resin, e.g. quaternary ammoniumion exchange resin, in the hydroxide cycle, to yield the correspondingdiazabicycloalkenonium hydroxide. The thus obtained hydroxide is treatedwith one equivalent of the acid of the desired anion, such as HCl, HBr,acetic acid, and the like. Alternatively, the sulfonate salt can betreated with a quaternary ammonium ion exchange resin in chloride,bromide, sulfate form, etc. to give the corresponding chloride, bromide,and sulfate salt, etc.

As in the case of the alkyl halide, the methanesulfonyloxy and thep-toluenesulfonyloxy may be attached to a primary or secondary carbon,and, for similar reasons, the primary carbon substituted form ispreferred, especially the primary carbon substituted form of thestraight chain alkanes.

The C -C halogenated alkanes used in preparing the halide salts of thisinvention can be obtained either commercially, or prepared by thehalogenation of an alcohol of the desired chain length with such agentsas hydrochloric acid, hydroiodic acid, phosphorus trichloride,phosphorus tribromide, thionylchloride, and the like. For a descriptionof these preparations, (and others), see Wagner and Zook, SyntheticOrganic Chemistry, John Wiley & Sons, Inc., pp. 88-147 (1953). The starting alcohols can be obtained commercially, prepared by the reduction ofa fatty acid of the desired chain length, or prepared by other wellknown techniques, such as those disclosed by Nazarov et al., Zhur.Obshchei Khim., 30, 443-50 (1960), Miller et al, Ind. Eng. Chem., 53,33-6 (1961), and Milburn et al, J. Chem. Soc., 1954, 334451.

The methanesulfonyloxy alkane is prepared by reducing a. fatty acid ofthe desired chain length to the corresponding alcohol, and thensubsequently reacting the thus obtained alcohol withmethanesulfonylchloride in anhydrous pyridine at room temperature.Fieser and Fieser, Reagents for Organic Synthesis, John Wiley & Sons,Inc., page 662 (1967). The p-toluenesulfonyloxy alkane is prepared in asimilar manner.

The diazabicycloalkenes of Formula (B) are commercially available, or ifdesired, can be synthesized using the procedures as set forth by Oedigeret al, Chem. B'er., 99, 2012 (1966) or Oediger and Moller, Angew. Chem.Internat, Edit, 6, No. 1, 76 (1967).

In the preparation of the compounds of the present invention, thereaction between the substituted alkanes and the diazabicycloalkene canbe carried out in the absence of solvent, or in an organic solvent inertto the reaction, such as benzene, toluene, petroleum ether, diglyme,hexane, pentane, xylene, tetrahydrofuran, methylethyl ketone, and thelike, and mixtures thereof.

The reaction is carried out at from room temperatures to the refluxtemperature of the reaction mixture, usually not higher than 150 C.Preferably, the reaction is carried out under anhydrous conditions andin the absence of air, e.g., by reacting under nitrogen, to minimize theformation of side products.

The particular reaction temperature selected will depend upon theparticular substituted alkane to be reacted as well as the particularsolvent. Reaction times will vary depending upon the nature of thereactants, the reaction temperature, and the particular solvent, usuallyranging from several minutes to an hour or more. The optimum temperatureand time of reaction can easily be determined by routine experimentationonce the particular reactants and solvent have been selected. By way ofexample, the reaction of the diazabicycloalkene with alkyl iodideproceeds easily at room temperature. The alkyl bromides and alkylchlorides normally are reacted under reflux in order to obtain optimumyields within reasonable lengths of time.

The molar ratio of sulfonyl or halo alkane to diazabicycloalkene is notcritical but typically is in the range of about from .1 to 10 mols ofsulfonyl or halo alkane to diazabicycloalkene. As the reaction isessentially st0ichiometric, a molar ratio of about 1:1 is preferred. Toensure complete reaction, a molar excess of either one of the reactantsmay be added to the reaction mixture. Generally, a molar excess of theleast expensive of the reactants should be added. However, unnecessaryexcesses should be avoided, as such results in a product mixturecontaining the quaternary ammonium salt and unreacted ingredients whichtypically are eventually sep arated.

The order of addition of reactants is immaterial. They may be added tothe reaction zone in any order, either singly or premixed.

Once the reaction is complete, the product is recovered by conventionaltechniques. For example, the product mixture can be cooled, solvent andany remaining reactants removed by distillation in high vacuum and theresulting solid crystalline material directly recrystallized. Otherrecovery techniques include thin layer or partition chromatography.

The quarternary ammonium salts of the present invention areanti-bacterial, antiviral, antiparasitic, and antiseptic. They areeffective against bacteria and fungi, such as Bacillus subtilis,Staphylococcus aareus, Escherichia coli, Proteus vulgaris, Salmonellaparatyphi, Pseudomonas aeruginosa, Shigella sonnei, Microsporum gypseum,Candida albicans, T richophytom mentagrophytes, Streptococcus pyogenes,Diplococcus pneumonia, N. Asteroides, Cr. neoformans, and S. schenshii.The novel compounds are effective in controlling bacteria and fungiwithin a wide dosage range. Depending upon such factors as the degreeand severity of infection, type of bacteria or fungi, the quaternaryammonium salts of the present invention are biocidal or biostatic. Theycan be used in solutions, sprays, and the like for disinfectinginanimate objects or can be used topically in the form of ointments,creams, solutions, sprays, and the like for treating bacterialinfections of animals.

A further understanding of the invention can be had from the followingexamples.

EXAMPLE 1 Into a ml. flask is placed 8 g. of hexadecylbromide, 3.26 g.of 1,5-diazabicyclo[4.3.0]non-5-ene and 50 ml. of benzene. The reactantsare heated under reflux and nitrogen for approximately 3 hours. Thesolution is then cooled under nitrogen and diluted with hexane until itbecomes cloudy. The product appears as a fine, pearlescent precipitateupon further cooling to approximately 10 C. The suspension is thencentrifuged for 10 minutes at 10,000 r.p.m. at approximately 8 C., thesupernatant decanted, and the white precipitate re-suspended in coldhexane and recentrifuged. This procedure is repeated, the supernatantdecanted, and the precipitate dried for 25 hours at room temperature andunder high vacuum to yield 7.945 grams of white pearlescent product,S-hexadecyl-l,S-diazabicyclo [4.3.0]nonenonium bromide. The decantedliquid fractions are combined and evaporated under reduced pressure. Theresulting clear oil is dissolved in tetrahydrofuran and cooled to 10 C.to give a precipitate, which is filtered under nitrogen at 4 C., washedwith hexane and vacuum dried at room temperature to yield 0.748 grams ofsolid product comprising S-hexadecyl-1,5-diazabicyclo- [4.3.0]nonenoniumbromide.

, '5 EXAMPLE 2 a J N 3 Following the procedures as set. forthin Example1, hexadecyl bromide is reacted with 1,5 :-,diaz'abicyclo[5.4 ,0]-undec-S-ene and 1,5-diazabicyclo [4.4.0]dec-5-ene to yield respectively5 hexadecyl-1,5-diazabicyclo[5.4.0]undece- 5 nonium bromide and 5-hexadecyl 1,5 diazabicyclo[4.4.0]- decenonium bromide. T etracosylbromide is reacted with a molar equivalent of1,5-diazabicyclo[5.4.0]undecr5-ene to yield 5tetracosyl-1,S-diazabicyelo[5.4.0]undecenonium bromide. Octadecylbromide is reacted with 1,5-diazabicycl[4.4.'0]undec-5-ene and1,5-diazabicyclo[4.3.0]non-- ene-"to yield5-octadecyl-1,S-diazabicyclo[4.4.0]undecenonium bromide andS-oetadeeyl-1,5-diazabicyclo [4.3.0]- nonenonium bromide, respectively.

EXAMPLE 3 To 2.3 g. of decylchloride in a 50 ml. flask, is added 1.63 g.of 1,5-diazabicyclo[4.3.0]non-5-ene and 25 ml. of benzene. The mixtureis refluxed under nitrogen for 12 hours. The resulting product is thenevaporated under reduced pressure followed by the application of highvacuum at 40 C.

The solid product is slurried with 100 ml. of hexane and filtered. Thisprocedure is repeated and the thus obtained solid is dried under reducedpressure. The resulting white powder consists ofS-decyl-1,5-diazabicyclo- [4.3.0]nonenonium chloride.

EXAMPLE 4 Into a 50 ml. flask is added 1.63 g. of diazabicyclodecene,4.71 g. of decyl iodide and 25 ml. of hexane. The reaction is allowed toproceed under nitrogen atmosphere and at room temperature for about ahalf hour. The reaction mixture is then subject to evaporation underreduced pressure. The remaining solid product is suspended in toluene,filtered, and washed several times with additional toluene. The washedsolid product is then dried in high vacum. The resulting white powdercomprises 5-decyl-l,5- diazabicyclo [4.4.0] decenonium iodide.

In a similar manner, tetracosyl iodide is reacted with1,5-diazabicyclo[4.3.0]non-5-ene to obtain S-tetracosyl-1,5-diazabicyclo[4.3.0] nonenonium iodide.

EXAMPLE 5 Following the procedure set forth in Example 1, 14-methylpentadecyl chloride, 3,3-dimethyldecyl chloride, 5,9-dimethyldecylchloride, 4,10-dimethyldodecyl bromide, 3,7,ll-trimethyldodecyl bromide,lo-methylundecyl i0- dide, 12-methy1tridecyl bromide, 20-methyltricosylbromide, 18-methyleicosyl chloride, 6-pentylundecyl iodide, hexadecylchloride, decyl chloride and dodecyl iodide are separately reacted with1,5-diazabicyclo[4.4.0]dec-S-ene to yield respectively,

5- 14'-methylpentadecyl) -l,5-diazibicyclo [4.4.0] decenonium chloride,

5- (3 ',3 '-dimethyldecyl) -1,5-diazabicyclo [4.4.0] decenoniumchloride,

5 5 ',9'-dimethyldecy1) -l,5-diazabicyclo [4.4.0] deceneonium chloride,

5- (4,l 0'-dimethyldodecyl) 1,5-diazabicyclo [4.4.0]

decenonium bromide,

5- (3 ',7',1 l'-trimethyldodecyl)-1,5-diazabicyclo [4.4.0]

decenonium bromide,

5-( -methylundecyl) -1,5-diazabicyclo [4.4.0] decenonium iodide,

5-( l2'-methyltridecyl) -1,5-diazabicyclo [4.4.0] decenonium bromide,

5- 20'-methyltricosyl) -1,5-diazabicyclo [4.4.0] decenonium bromide,

5- 18'-methyleicosyl) -1,5-diazabicyclo [4.4.0] decenonium chloride,

5-(6'-pentylundecyl)-1,5-diazabicyclo [4.4.0] deceneonium iodide,

S-hexadecyl-l ,S-diazabicyclo [4.4.0] decenonium chloride,

5-dodecyl-1,5-diazabicyclo [4.4.0] decenonium iodide.

6 EXAMPLE 6 13yv the methods as outlined above, 10 g. of methanesul fonyloxy decane is reacted with 6g. of 1,5-diazabicyclo [4.4.0] dec-S-ene.The residue, 5.-decyl 1,5 diazabicyclo [4.4.0]decenoniummethanesulfonate', is dissolved in methanol and filtered slowly througha'column of a quaternary ammonium ion exchange resin sold under thetrademark Dowex 2-X8 (30 grams of resin, chloride form). The resultingeluate is vaporated under vacuum to yieldthe chloride salt,5-decyl-1,5-diazabicyclo [4.4.0] decenonium chloride. The filtrationprocedure is repeated for fresh methanesulfonate, the column containing30 g. of ion exchange resin (sulfate form) sold under the trademarkDowex 2-X8 5-decyl-l,5-diazabicyclo[4.4.0] decenonium sulfate.

In a similar manner, 1 g. of p-toluenesulfonyloxy decane is reacted with4 g. of 1,5-diazabicyclo[4. 3.0]non-5- ene to yield 5decyl-l,5-diazabicyclo[4.3.0]nonenonium p-toluenesulfonate. The ptoluenesulfonate salt is filtered through a column of ion exchange resin(chloride form) sold under the trademark Dowex 2-X8, ad the dried toyield S-decyl-l,5-diazabiocyclo[4.3.0]nonenonium chloride.

EXAMPLE 7 Following the procedures of Example 1, substituting hexadecylchloride for hexadecyl bromide, a white solid product, 5hexadecyl-S-diazabicyclo[4.3.0]nonenonium chloride is obtained. Thisproduct is dissolved in methanol and filtered through a column of 20 g.of ion exchange resin (OH form) sold under the trademark Dowex 2-X 8.The resulting diazabicyclo[4.3.0]nonenonium hydroxide eluate is treatedwith one equivalent of aqueous hydrobromic acid and the solventsevaporated to yield the corresponding diazabicyclo [4.3.0] nonenoniumbromide.

Addition of one equivolent of acetic, propionic, lactic, benzoic andnicotinic acids to separate portions of diazabicyclo[4.3.0]nonenoniumhydroxide yields respectively the acetate, propionate, lactate, henzoateand nicotinate salts thereof.

Obviously many modifications and variations of the invention describedhereinabove and in the appended claims can be made without departingfrom the essence and scope thereof.

Having thus described the invention, what we claim is:

1. A quaternary ammonium salt of the formula:

(Cl-l n wherein R is a straight chain alkyl of 10 to 24 carbon atoms ora branched alkyl of 10 to 24 carbon atoms in the longest chain andhaving one or more branched groups selected from the group consisting ofalkyls having from one to eight carbon atoms; n is a positive integer offrom one to three; and Y is a non-toxic anion.

2. The salt of claim 1 wherein R is a straight chain C o-C24 alkyl.

3. The salt of claim 2 wherein Y is selected from the group consistingof chloride, bromide, methanesultonyloxy, and p-toluenesulfonyloxy.

4. The S-decyl-1,5-diozabicyclo[4.3 .0] nonenonium chloride of claim 1.

5. The 5-decyl-1,5-diazabicyclo [4.4.0]decenonium chloride of claim 1.

6. The S-decyl-1,5-diazabicyclo[5.4.0]undecenonium chloride of claim 1.

7. The 5 dodecyl-1,5-diazabicycl0[4.3.0]nonenonium chloride of claim 1.

8. The 5-dodecyl-1,S-diazabicyclo[4.4.0]decenonium chloride of claim 1.

9. The S-tetradecyl-1,5-diazabicyclo[4.3.0]nonenonium chloride of claim1.

10. The S-tetradecyl-1,5-diazabicyclo [4.4.0]decenonium chloride ofclaim 1.

11. The S-tetradecyl-1,5-diazabicyclo[5.4.0]undecenonium chloride ofclaim 1.

12. The S-hexadecyl-1,5-diazabicyclo [4.3 .0] nonenonium chloride ofclaim 1.

13. The S-hexadecyl-1,5-diazabicyclo[4.4.0]decenonium chloride of claim1.

14. The S-hexadecyl-1,5-diazabicyclo[5.4.0]undecenonium chloride ofclaim 1.

15. The 5 -octadecyl-l,S-diazabicyclo[4.3.0]nonenonium chloride of claim1.

References Cited FOREIGN. PATENTS 7/1967 France.

OTHER REFERENCES Kirk-Othmer: Encyclopedia of Chemical Technology, vol.11, pp. 380-381 (1953), Interscience Publishers.

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R.

